A comparative study on the metabolism ofd-limonene and 4-vinylcyclohex-1-ene by hepatic microsomes

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Abstract
Rat liver microsomes converted d-limonene [a major component in many essential oils of citrus fruits] to the 1,2-epoxide (1-methyl-4-(1''-methylethenyl)-7-oxabicyclo[4,1,0]heptane), the 8,9-epoxide (1-methyl-4-(1''-methyl-1'',2''-epoxyethyl)cyclohex-1-ene) and the 8,9-glycol (2-(4''-methylcyclohex-3''-en-1''-yl)propane-1,2-diol) in the presence of NADPH. The 8,9-glycol was formed in the highest yield, the 1,2-epoxide in next highest yield and the 8,9-epoxide was formed in low yield. The absence of the 1,2-glycol (1-methyl-4-(1''-methylethenyl)cyclohexene-1,2-diol) as a microsomal metabolite of d-limonene was attributed to the fact that microsomal hydrolysis of the 1,2-epoxide occurs at about 1% of the rate for the 8,9-epoxide. The epoxide hydrolase inhibitor, 3,3,3-trichloropropene 1,2-oxide, completely inhibited microsomal hydrolysis of the 8,9-epoxide formed from d-limonene and resulted in its accumulation in the reaction medium without yielding any detectable amount to the 8,9-glycol. From comparison with a study on the microsomal metabolism of 4-vinylcyclohex-1-ene, the biological selectivity in the microsomal oxidation of the d-limonene double bonds was attributed to a steric hindrance effect of the C1-methyl group. In the less hindered 4-vinylcyclohex-1-ene molecule, microsomal epoxidation occurred preferentially at the C1-double bond, a site readily epoxidizable by chemical oxidants. Hydrolysis of 4-vinylcyclohex-1-ene epoxides by microsomal epoxide hydrolase also occurred at a higher rate with the less alkyl-substituted vinyl epoxide moiety. d-Limonene, 4-vinylcyclohex-1-ene and their epoxides were all non-mutagenic toward Salmonella typhimurium TA 98, TA 100, TA 1535, TA 1537 and TA 1538 in the presence and in the absence of a PCB[polychlorinated biphenyl]-induced rat liver 9000 g supernatant fraction fortified with a NADPH-generating system.